Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors.
The neuropeptide receptor for substance P (NK-1) is widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes.
The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson""s disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645).
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer""s disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn""s disease, ocular injury and ocular inflammatory diseases reviewed in xe2x80x9cTachykinin Receptor and Tachykinin Receptor Antagonistsxe2x80x9d, J. Auton. Pharmnacol., 13, 23-93, 1993.
Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).
The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting. The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 has been described the reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. U.S. Pat. No. 5,972,938 describes a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist.
This invention relates to compounds of the general formula 
wherein
R is lower alkyl, lower alkoxy, halogen or trifluoromethyl;
R1 is halogen or hydrogen; and when p is 1, R1 may in addition to the above substituents be taken together with R to form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94
R2 and R2xe2x80x2 are independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano;
and when n is 1, R2 and R2xe2x80x2 may in addition to the above substituents form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, unsubstituted or substituted by one or two substituents selected from lower alkyl or lower alkoxy,
R3 and R3xe2x80x2 are hydrogen, lower alkyl or taken together with the attached carbon atom form a cycloalkyl group;
R4 is hydrogen, xe2x80x94N(R5)2, xe2x80x94N(R5)(CH2)nOH, xe2x80x94N(R5)S(O)2-lower alkyl, xe2x80x94N(R5)S(O)2-phenyl, xe2x80x94Nxe2x95x90CHxe2x80x94N(R5)2, xe2x80x94N(R5)C(O)R5, 
R5 is hydrogen, C3-6-cycloalkyl, benzyl or lower alkyl;
R6 is hydrogen, hydroxy, lower alkyl, xe2x80x94(CH2)nCOOxe2x80x94(R5), xe2x80x94N(R5)COxe2x80x94lower alkyl, hydroxy-lower alkyl, xe2x80x94(CH2)nCN, xe2x80x94(CH2)nO(CH2)nOH, xe2x80x94CHO or a 5-or 6 membered heterocyclic ring containing from 1 to 4 heteroatoms, selected from the group consisting of oxygen, nitrogen, and sulfur, and with one of the carbon atoms in said ring being unsubstituted or substituted with an oxo group, which hetercyclic ring is directly bonded or bonded via an alkylene group to the remainder of the molecule; 
xe2x80x83is a cyclic tertiary amine which may contain one additional heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur, wherein any sulfur present in the ring is thio or can be oxidized to sulfoxide or sulfur dioxide by which said cyclic tertiary amine is directly attached to the remainder of the molecule or is attached through the linker xe2x80x94(CH2)nN(R5)xe2x80x94;
X is xe2x80x94C(O)N(R5)xe2x80x94, xe2x80x94(CH2)mOxe2x80x94, xe2x80x94(CH2)mN(R5)xe2x80x94, xe2x80x94N(R5)C(O)xe2x80x94, or xe2x80x94N(R5)(CH2)mxe2x80x94;
n, p and q are 1 to 4; and
m is 1 or 2;
and pharmaceutically acceptable acid addition salts thereof, which are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.
This invention includes compounds and pharmaceutically acceptable salts thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of symptoms associated with certain conditions and diseases.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom.
The term xe2x80x9chalogenxe2x80x9d denotes chlorine, iodine, fluorine and bromine.
The term xe2x80x9ccycloalkylxe2x80x9d denotes a saturated carbocyclic group (e.g. a nonaromatic ring), preferably containing 3-6 carbon atoms (i.e. C3-C6 cycloalkyl).
A xe2x80x9ccyclic tertiary aminexe2x80x9d denotes a ring system which may contain one additional heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur, wherein any sulfur present in the ring is thio or can be oxidized to sulfoxide or sulfur dioxide by which said cyclic tertiary amine, which ring is directly attached via the ring nitrogen to the remainder of the molecule or is attached through the linker xe2x80x94(CH2)nN(R5)xe2x80x94.
The cyclic tertiary amine may contain three to five carbon atoms. When the ring is substituted it is preferably substituted at the heteroatom, for example N-alkyl-piperazine. Examples of such rings include pyrrol-1-yl, imidazol-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, 1-oxo-thiomorpholin-4-yl or 1,1-dioxo-thiomorpholin-4-yl.
When R4 is substituted (as in for example xe2x80x9csubstituted piperazinylxe2x80x9d), the substituent is R6, as defined above.
The term a xe2x80x9c5-or 6 membered hetercyclic ringxe2x80x9d is a ring system, which contains from 1 to 4 heteroatoms, selected from the group consisting of oxygen, nitrogen, and sulfur, and with one of the carbon atoms in said ring being unsubstituted or substituted with an oxo group. Examples of such rings are pyrimidine, oxadiazole, triazole, tetrazole, pyridine, thiazole, thiene, furane, pyrane, pyrrole, imidazole, pyrazole, isothiazole, piperazine or piperidine.
When R6 is R6xe2x80x2 (a 5 or 6 membered heterocyclic ring) is bonded via an alkylene group to the remainder of the molecule, this phrase designates the substituent R6xe2x80x2 linked to a CH2 (for example) linked to the 
ring, e.g. 
The term xe2x80x9calkylenexe2x80x9d denotes a lower alkyl linker which is bound to a group at either end.
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
Compounds of this invention are NK-1 receptor antagonists and, as such, are particularly useful for treating depression and pain, especially that resulting from inflammatory conditions such as migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease or resulting from central nervous system (CNS) disorders such as Parkinson""s disease or Alzheimer""s disease.
Furthermore, the compounds of this invention are useful as agent against headache, anxiety, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn""s disease, ocular injury and ocular inflammatory diseases.
The compounds of formula I are further useful for the treatment of motion sickness and emesis.
Thus the most preferred indications in accordance with the present invention are those which include disorders of the central nervous system, for example indications for the treatment or prevention of certain depressive disorders, anxiety or emesis by the administration of NK-1 receptor antagonists. A major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either depressed mood or the loss of interest or pleasure in all, or nearly all activities.
Accordingly this invention is directed to the NK-1 receptor antagonists of formula 1.
Preferred compounds of this invention include compounds of formula I where R is lower alkyl, lower alkoxy, halogen or trifluoromethyl and R1 is halogen or hydrogen, or compounds where R2 and R2xe2x80x2 are independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano.
Particularly preferred are compounds where R, R1, R2, and R2xe2x80x2 are as described immediately above (i.e. R is lower alkyl, lower alkoxy, halogen or trifluoromethyl, R1 is halogen or hydrogen, and R2 and R2xe2x80x2 are independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano).
In some of these particularly preferred compounds, X is N(R5)C(O)xe2x80x94.
Examples of these particularly preferred compounds where R4 is hydrogen are 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(4-o-tolyl-pyridin-3-yl)-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-acetamide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-propionamide, 1-(3,5-Bis-trifluoromethyl-phenyl)-cyclopropanecarboxylic acid [4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amide.
In other such particularly preferred compounds where X is N(R5)C(O)xe2x80x94, R4 is 
preferably a five-membered or a six-membered tertiary amine ring, for example unsubstituted or substituted piperazinyl, morpholino, thiomorpholino, piperidinyl, or pyrrolidinyl. Examples of the piperazinyl compounds are 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-pyrimidin-2-yl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, [2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propyl]-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-methyl-amine.
Examples of morpholino compounds are 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-acetamide, 2-(3,5-Dimethoxy-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-acetamide, 2-(3-Fluoro-5-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-acetamide.
Examples of unsubstituted or substituted piperidinyl compounds are 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4xe2x80x2-(2-chloro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyridinyl-5xe2x80x2-yl]-N-methyl-isobutyramide and 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4xe2x80x2-(2-chloro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyridinyl-5xe2x80x2-yl]-N-methyl-isobutyramide.
An example of a pyrrolidinyl compound is 2-(3,5-bis-trifluoromethyl-phenyl)-N-{6-[(2-hydroxy-ethyl)-methyl-amino]-4-6-tolyl-pyridin-3-yl}-N-methyl-isobutyramide.
In certain particularly preferred compounds where X is N(R5)C(O)xe2x80x94 and R4 is 
R4 is attached through the linker xe2x80x94(CH2)nN(R5)xe2x80x94.
An example of such a compound is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-{6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-pyridin-3-yl}-isobutyramide.
In yet other such particularly preferred compounds where X is N(R5)C(O)xe2x80x94, R4 is xe2x80x94N(R5)2, xe2x80x94N(R5)(CH2)nOH, xe2x80x94N(R5)S(O)2-lower alkyl, N(R5)S(O)2-phenyl, xe2x80x94Nxe2x95x90CHxe2x80x94N(R5)2, xe2x80x94N(R5)C(O)R5. Such compounds include 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6-dimethylamino-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-dimethylamino-pyridin-3-yl]-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-{6-[(2-hydroxy-ethyl)-methyl-amino]-4-o-tolyl-pyridin-3-yl}-N-methyl-isobutyramide, N-(6-Benzylamino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, N-(6-Amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(dimethylamino-methyleneamino)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6-methanesulfonylamino-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide, N-(6-Benzenesulfonylamino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide.
In other particularly preferred compounds (i.e. compounds where R is lower alkyl, lower alkoxy, halogen or trifluoromethyl, R1 is halogen or hydrogen, and R2 and R2xe2x80x2 are independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano), X is xe2x80x94C(O)N(R5)xe2x80x94.
In some of these compounds, R4 is hydrogen. Such compounds include N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-(2-chloro-phenyl)-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-(2-trifluoromethyl-phenyl)-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-(2-fluoro-phenyl)-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-(2-fluoro-phenyl)-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-phenyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-ethyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-cyclopropyl-4-o-tolyl-nicotinamide, N-[1-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-di-Fluorobenzyl)-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-di-Chlorobenzyl)-N-methyl-4-o-tolyl-nicotinamide.
In other particularly preferred compounds where X is xe2x80x94C(O)N(R5)xe2x80x94R4 is 
preferably a five-membered or a six-membered tertiary amine ring, for example unsubstituted or substituted piperazinyl, morpholino, thiomorpholino, piperidinyl, or pyrrolidinyl. Examples of compounds where R4 is unsubstituted or substituted piperazinyl are N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamide, 4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridin-2-yl}-piperazine-1-carboxylic acid, 4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridin-2-yl}-piperazine-1-carboxylic acid, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-propyl-piperazin-1-yl)-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-cyanomethyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-6-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazin-1-yl}-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-[1,2,4]oxadiazol-3-ylmethyl-piperazin-1-yl)-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-[1,2,4]oxadiazol-3-ylmethyl-piperazin-1-yl)-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-formyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-[4-(1H-tetrazol-5-ylmethyl)-piperazin-1-yl]-4-o-tolyl-nicotinamide.
Examples of compounds where R4 is morpholino or substituted morpholino are N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide, N-(2-Methoxy-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide, N-(5-Chloro-2-methoxy-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide, N-(2-Chloro-5-methoxy-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide, N-(2-Chloro-5-methoxy-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide, N-[2-Methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide.
Examples of compounds where R4 is thiomorpholino or oxidized thiomorpholino are N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-thiomorpholin-4-yl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(1-oxo-1xcex4-thiomorpholin-4-yl)-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-6-(1,1-dioxo-1xcex6-thiomorpholin-4-yl)-N-methyl-4-o-tolyl-nicotinamide.
Examples of compounds where R4 is unsubstituted or substituted piperidinyl are 5xe2x80x2-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4xe2x80x2-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyridinyl-4-carboxylic acid and 5xe2x80x2-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4xe2x80x2-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyridinyl-4-carboxylic acid.
An example of a compound where R4 is unsubstituted or substituted pyrrolidinyl is (RS)-6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-4-o-tolyl-nicotinamide.
In certain particularly preferred compounds where X is xe2x80x94C(O)N(R5)xe2x80x94 and R4 is 
R4is attached through the linker xe2x80x94(CH2)nN(R5)xe2x80x94.
An example of such a compound is N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-nicotinamide.
In yet other such particularly preferred compounds where X is xe2x80x94C(O)N(R5)xe2x80x94, R4 is xe2x80x94N(R5)2, xe2x80x94N(R5)(CH2)nOH, xe2x80x94N(R5)S(O)2-lower alkyl, N(R5)S(O)2-phenyl, xe2x80x94Nxe2x95x90CHxe2x80x94N(R5)2, xe2x80x94N(R5)C(O)R5.
In yet other particularly preferred compounds (i.e. compounds where R is lower alkyl, lower alkoxy, halogen or trifluoromethyl, R1 is halogen or hydrogen, and R2 and R2xe2x80x2 are independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano), X is xe2x80x94(CH2)mOxe2x80x94. Preferably R4 is hydrogen.
An example of such a compound is 3-(3,5-bis-trifluoromethyl-benzyloxymethyl)-4-o-tolyl-pyridine.
In further particularly preferred compounds X is xe2x80x94(CH2)mN(R5)xe2x80x94. Preferably R4 is hydrogen.
An example of such a compound is (3,5-bis-trifluoromethyl-benzyl)-methyl-(4-o-tolyl-pyridin-3-ylmethyl)-amine.
In another such compound, (3,5-bis-trifluoromethyl-benzyl)-[4-(2-chloro-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-methyl-amine, R4 is substituted piperazin.
In certain compounds of formula 1 where R is lower alkyl, lower alkoxy, halogen or trifluoromethyl and R1 is halogen or hydrogen, R2 and R2xe2x80x2 together form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, unsubstituted or substituted by one or two substituents selected from lower alkyl or lower alkoxy. Preferably X is xe2x80x94C(O)N(R5)xe2x80x94. More preferably, R is lower alkyl, R1 is hydrogen, R3 and R3xe2x80x2 are hydrogen, and R4 is morpholino. Such compounds are N-Methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nicotinamide, N-Methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nicotinamide, N-(2-Methoxy-naphthalen-1-ylmethyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide, N-(2-Methoxy-naphthalen-1-ylmethyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide, N-(1,4-Dimethoxy-naphthalen-2-ylmethyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide.
In certain other compound of formula 1 where R2 and R2xe2x80x2 are independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano, R and R1 together form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94. Preferably X is xe2x80x94C(O)N(R5)xe2x80x94. More preferably, R2 and R2xe2x80x2 are trifluoromethyl; R3 and R3xe2x80x2 are hydrogen, and R4 is piperazinyl substituted with lower alkyl.
Such a compound is N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-naphthalen-1-yl-nicotinamide.
In certain preferred compounds, R is halogen or lower alkyl. It is also preferred that R1 is hydrogen. Preferred substituents at R2 and R2xe2x80x2 are trifluoromethyl or halogen. Preferred substituents at R3 and R3xe2x80x2 are hydrogen or lower alkyl. It is also preferred that R5 is lower alkyl. For X xe2x80x94N(R5)C(O)xe2x80x94 is preferred. Preferably any combination of these substituents are found, for example R is halogen and R2 and R2xe2x80x2 are trifluoromethyl or halogen, and other combinations of the above substituents. In especially preferred compounds, all of the above are true, i.e. R is halogen or lower alkyl, R1 is hydrogen, R2 and R2xe2x80x2 are trifluoromethyl or halogen, R3 and R3xe2x80x2 are hydrogen or lower alkyl, and X is xe2x80x94N(R5)C(O)xe2x80x94 is preferred. In particular in such compounds, R5 is preferably lower alkyl.
Examples of such compounds are 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide (where R4 is 4-methyl-piperazin-1-yl), 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide (where R4 is hydrogen) and 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide (where R4 is unsubstituted morpholino).
An embodiment of this invention is 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, the compound of formula I which has the formula: 
and to pharmaceutically acceptable acid addition salts thereof.
This compound of formula Ia and its salts are characterized by valuable therapeutic properties as a highly selective antagonist of the Neurokinin 1 (NK-1, substance P) receptor. As described earlier, such activity is particularly useful for treating CNS disorders, such as depression, anxiety or emesis.
The present compound of formula Ia and its pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
a) reacting the compound of formula 
with the compound of formula 
to the compound of formula 
and, if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt.
In accordance with process variant a) DIPEA (N-ethyldiisopropyl-amine) is added to a mixture of the compound of formula II and the compound of formula III in dichloromethane and the mixture is stirred at temperatures between 35-40xc2x0 C. The desired compound of formula I is yielded after purification in good yields.
The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids are possible. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methanesulphonates, p-toluenesulphonates and the like are examples of such salts.
The following schemes 1 and 2 and example 23 describe the processes for the preparation of the compound of formula Ia in more detail. The starting materials of formulae III, IV and VII are known compounds or may be prepared according to methods known in the art.
In the schemes the following abbreviations have been used:

The affinity of compound of formula 1a for the NK1 receptor was evaluated at human NK1 receptors in CHO cells infected with the human NK1 receptor (using the Semliki virus expression system) and radiolabelled with [3H]substance P (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%), leupeptin (8 xcexcg/ml), MnCl2 (3 mM) and phosphoramidon (2 xcexcM). Binding assays consisted of 250 xcexcl of membrane suspension (1.25xc3x97105 cells/assay tube), 0.125 xcexcl of buffer of displacing agent and 125 xcexcl of[3H]substance P. Displacement curves were determined with at least seven concentrations of the compound. The assay tubes were incubated for 60 min at room temperature after which time the tube contents were rapidly filtered under vacuum through GF/C filters presoaked for 60 min with PEI (0.3%) with 2xc3x972 ml washes of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in triplicate in at least 2 separate experiments.
The compound of formula Ia is a potent and selective antagonist at recombinant human neurokinin, (NK1) receptors expressed in CHO cells. It has an affinity (pKi) of 9.0 for the human NK1 receptor over 2 orders of magnitude of selectivity for the NK1 receptor compared to NK2 and NK3 receptors and compared to over 50 other binding sites that have been evaluated.
The following assays may be used for further screening for any compound of this invention to determine in vivo activity.
The activity in vitro of the compound of formula 1a was examined by studying its effect on substance P induced Ca2+ influxes in CHO cells expressing the recombinant human NK1 receptor. In these cells, substance P causes a concentration dependent influx of Ca2+ which can be measured using FLIPR technology. Increasing concentrations of 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide cause a rightward shift in the concentration effect curve of substance P. Expressing these data on a Schild plot allows the calculation of the antagonist affinity (pA2) for this compound of 8.9 (slope of the Schild regression=1.1). These data indicate that 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide is a competitive antagonist at human recombinant NK1 receptors.
In vivo the compound of formula Ia antagonises foot-tapping behaviour induced in gerbils with intracerebroventricular (i.c.v.) injections of an NK1 receptor agonist. The dose for this compound calculated to inhibit 50% of the foot-tapping behaviour following oral administration was 0.2 mg/kg. The plasma levels required to completely antagonise this behaviour have also been measured and it was found that a total plasma concentration of 10 ng/ml is required to completely block the foot-tapping behavoiur. This antagonism persisted for a number of hours and had a functional half life of 8 hours in this model.
The compound of formula 1a, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, was also tested as an antiemetic agent in ferrets. Emesis was induced in ferrets by various emetogens (apomorphine, morphine, ipecacuanha, cisplatin and CuSO4. Pretreatment with this compound (0.3 mg/kg, p.o.) 2 hours before the emetigen, completely blocked the emesis induced by all emetogens. A full dose-response curve was constructed against apomorphine-induced emesis and an ED50 dose of 0.1 mg/kg, p.o. was calculated.
In a model of motion sickness in the suncus murinus, the compound was found to have an ED50 of 0.2 mg/kg, p.o.
Therefore, in conclusion, 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide is a potent antagonist of NK1 induced behaviours in gerbils and blocks emesis in ferrets and suncus murinus with similar potency.
The pharmacokinetic parameters have been evaluated in both rats and dogs. In rats, the compound has a terminal half-life of 23 hours, a clearance of 4 ml/min/kg, a volume of distribution of 8 l/kg and an oral bioavailability of 50%. In dogs the molecule had a half-life of 40 hours, a clearance of 16 ml/min/kg, a volume of distribution of 22 l/kg and an oral bioavailability of 30-40%.
Another embodiment of this invention is a compound of formula I (2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide) which has the formula Ib 
and to pharmaceutically acceptable acid addition salts thereof.
The compound of formula Ib and its salts is also characterized by valuable therapeutic properties as a highly selective antagonist of the Neurokinin 1 (NK-1, substance P).
The present compound of formula Ib and its pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
a) reacting the compound of formula 
with the compound of formula 
to the compound of formula 
and,
if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt.
In accordance with process variant a) DIPEA (N-ethyldiisopropyl-amine) is added to a mixture of the compound of formula II and the compound of formula III in dichloromethane and the mixture is stirred at temperatures between 35-40xc2x0 C. The desired compound of formula I is yielded after purification in good yields.
The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids are possible. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methanesulphonates, p-toluenesulphonates and the like are examples of such salts.
The following schemes 1 and 2 and example 14 describe the processes for the preparation of the compound of formula Ib in more detail. The starting materials of formulae III, IV and VII are known compounds or may be prepared according to methods known in the art.
In the schemes the following abbreviations have been used:

The affinity of the compound of formula Ib for the NK1 receptor was evaluated at human NK1 receptors in CHO cells infected with the human NK1 receptor (using the Semliki virus expression system) and radiolabelled with [3H]substance P (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%) leupeptin (8 xcexcg/ml), MnCl2 (3 mM) and phosphoramidon (2 xcexcM). Binding assays consisted of 250 xcexcl of membrane suspension (1.25xc3x97105 cells/assay tube), 0.125 xcexcl of buffer of displacing agent and 125 xcexcl of [3H] substance P. Displacement curves were determined with at least seven concentrations of the compound. The assay tubes were incubated for 60 min at room temperature after which time the tube contents were rapidly filtered under vacuum through GF/C filters presoaked for 60 min with PEI (0.3%) with 2xc3x972 ml washes of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in triplicate in at least 2 separate experiments.
The compound of formula Ib is a potent and selective antagonist at recombinant human neurokinin, (NK1) receptors expressed in CHO cells. It has an affinity (pKi) of 9.0 for the human NK1 receptor and over 2 orders of magnitude of selectivity for the NK1 receptor compared to NK2 and NK3 receptors and compared to over 50 other binding sites that have been evaluated.
The following assays may be used for further screening for any compound of this invention to determine in vivo activity.
The activity of 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide in vitro was examined by studying its effect on substance P induced Ca2+ influxes in CHO cells expressing the recombinant human NK1 receptor. In these cells, substance P causes a concentration dependent influx of Ca2+ which can be measured using FLIPR technology. The compound inhibited this effect in a concentration dependent manner. These data indicate that 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide is a competitive antagonist at human recombinant NK1 receptors.
In vivo 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide antagonises foot-tapping behaviour induced in Gerbils with intracerebroventricular (i.c.v.) injections of an NK1 receptor agonist. The dose of this compound calculated to inhibit 50% of the foot-tapping behaviour following oral administration was 0.5 mg/kg. The plasma levels required to completely antagonise this behaviour have also been measured and it was found that a total plasma concentration of 30 ng/ml is required to completely block the foot-tapping behavoiur. This antagonism persisted for a number of hours and had a functional half life of 30 hours in this model.
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide was also tested as an antiemetic agent in Ferrets. Emesis was induced in Ferrets by various emetogens (apomorphine, morphine, ipecacuanha, cisplatin and CuSO4. Pretreatment of this compound (0.3 mg/kg, p.o.) 2 hours before the emetigen, completely blocked the emesis induced by all emetogens. A full dose-response curve was constructed against apomorphine-induced emesis and an ED50 dose of 0.1 mg/kg, p.o. was calculated.
In a model of motion sickness in the suncus murinus, 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide was found to have an ED50 of 0.2 mg/kg, p.o.
Therefore, in conclusion, 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide is a potent antagonist of NK1 induced behaviours in Gerbil and blocks emesis in Ferrets and suncus murinus with similar potency.
The pharmacokinetic parameters have been evaluated in both rats and dogs. In rats, the compound has a terminal half-life of 24 hours, a clearance of 3.7 mL/min/kg, a volume of distribution of 5.7 l/kg and an oral bioavailability of 45%. In dogs the molecule had a half-life of 18 hours, a clearance of 9.2 ml/min/kg, a volume of distribution of 15 l/kg and an oral bioavailability of 75%.
Yet another embodiment of this invention is 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, the compound of formula 
and to pharmaceutically acceptable acid addition salts thereof.
The compound of formula Ic and its salts are characterized by valuable therapeutic properties. It has been found that the compound of the present invention is a highly selective antagonist of the Neurokinin 1 (NK-1, substance P) receptor.
The present compound of formula Ic and pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
a) reacting the compound of formula 
with the compound of formula 
to the compound of formula 
and,
if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt.
In accordance with process variant a) DIPEA (N-ethyldiisopropyl-amine) is added to a mixture of the compound of formula II and the compound of formula III in dichloromethane and the mixture is stirred at temperatures between 35-40xc2x0 C. The desired compound of formula Ic is yielded after purification in good yields.
The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids are possible. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methanesulphonates, p-toluenesulphonates and the like are examples of such salts.
The following schemes 1 and 2 and example 17 describe the processes for the preparation of the compound of formula Ic in more detail. The starting materials of formulae III, IV and VII are known compounds or may be prepared according to methods known in the art.
In the schemes the following abbreviations have been used:

The affinity of the compound of formula Ic for the NK1 receptor was evaluated at human NK1 receptors in CHO cells infected with the human NK1 receptor (using the Semliki virus expression system) and radiolabelled with [3H]substance P (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%) leupeptin (8 xcexcg/ml), MnCl2 (3 mM) and phosphoramidon (2 xcexcM). Binding assays consisted of 250 xcexcl of membrane suspension (1.25xc3x97105 cells/assay tube), 0.125 xcexcl of buffer of displacing agent and 125 xcexcl of [3H]substance P. Displacement curves were determined with at least seven concentrations of the compound. The assay tubes were incubated for 60 min at room temperature after which time the tube contents were rapidly filtered under vacuum through GF/C filters presoaked for 60 min with PEI (0.3%) with 2xc3x972 ml washes of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in triplicate in at least 2 separate experiments.
2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide is a potent and selective antagonist at recombinant human neurokinin, (NK1) receptors expressed in CHO cells. It has an affinity (pKi) of 8.6 for the human NK1 receptor over 2 orders of magnitude of selectivity for the NK1 receptor compared to NK2 and NK3 receptors and compared to over 50 other binding sites that have been evaluated. The activity of the compound of formula Ic in vitro was examined by studying its effect on substance P induced Ca2+ influxes in CHO cells expressing the recombinant human NK1 receptor. In these cells, substance P causes a concentration dependent influx of Ca2+ which can be measured using FLIPR technology. 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide inhibited this effect in a concentration dependent manner. These data indicate that this compound is a competitive antagonist at human recombinant NK1 receptors.
In vivo the compound of formula Ic antagonises foot-tapping behaviour induced in Gerbils with intracerebroventricular (i.c.v.) injections of an NK1 receptor agonist. The dose of this compound calculated to inhibit 50% of the foot-tapping behaviour following oral administration was 1.5 mg/kg. The plasma levels required to completely antagonise this behaviour have also been measured and it was found that a total plasma concentration of 100 ng/ml are required to completely block the foot-tapping behavior.
Therefore, in conclusion, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide is a potent antagonist of NK1 induced behaviours in Gerbils.
The pharmacokinetic parameters have been evaluated in both rats and dogs. In rats, the compound of formula Ic has a terminal half-life of 11 hours, a clearance of 45 mL/min/kg, a volume of distribution of 2.6 l/kg and an oral bioavailability of xcx9c30%. In dogs the molecule had a half-life of 3.5 hours, a clearance of 30 ml/min/kg, a volume of distribution of 4.5 l/kg and an oral bioavailability of 16%.
Exemplary preferred are compounds, in which X is xe2x80x94C(O)N(R5)xe2x80x94, wherein R5 is methyl, ethyl or cyclopropyl, for example the following compounds: N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-(2-chloro-phenyl)-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-(2-trifluoromethyl-phenyl)-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-(2-fluoro-phenyl)-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-(2-methoxy-phenyl)-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-4-phenyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-ethyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-cyclopropyl-4-o-tolyl-nicotinamide, N-[1-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Di-fluorobenzyl)-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Di-chlorobenzyl)-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide, 2xe2x80x2-Methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoro-methyl-benzyl)-methyl-amide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-naphthalen-1-yl-nicotinamide, (4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridin-2-yl}-piperazin-1-yl)-acetic acid ethyl ester, 5xe2x80x2-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4xe2x80x2-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyridinyl-4-carboxylic acid ethyl ester, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-propyl-piperazin-1-yl)-4-o-tolyl-nicotinamide, (RS)-6-[3-(Acetyl-methyl-amino)-pyrrolidin-1-yl]-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-thiomorpholin-4-yl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(1-oxo-1l-4-thiomorpholin-4-yl)-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-6-(1,1-dioxo-1l-6-thiomorpholin-4-yl)-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-cyanomethyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-6-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazin-1-yl}-N-methyl-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-[1,2,4]oxadiazol-3-ylmethyl-piperazin-1-yl)-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-[4-(5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethyl)-piperazin-1-yl]-4-o-tolyl-nicotinamide, N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-formyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide and N-Methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nicotinamide.
Further preferred are compounds, in which X is xe2x80x94N(R5)xe2x80x94COxe2x80x94, wherein R5 is hydrogen or methyl.
Examples of such compounds are: 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(4-o-tolyl-pyridin-3-yl)-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-acetamide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-propionamide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-{6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-pyridin-3-yl}-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-pyrimidin-2-yl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-dimethylamino-pyridin-3-yl]-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(4-hydroxy-4xe2x80x2-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyridinyl-5xe2x80x2-yl)-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-{6-[(2-hydroxy-ethyl)-methyl-amino]-4-o-tolyl-pyridin-3-yl}-N-methyl-isobutyramide, (R)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide, 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin 3-yl)-acetamide and [2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propyl]-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-methyl-amine.
The present compounds of this invention and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
a) reacting a compound of formula 
with a compound of formula.
The present compounds of this invention and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
a) reacting a compound of formula 
with a compound of formula 
to a compound of formula 
wherein R1-R5, R and n have the significances given above, or
b) reacting a compound of formula 
with a compound of formula 
to give a compound of formula 
wherein R1-R5, R and n have the significances given above, or
c) reducing a compound of formula 
to a compound of formula 
wherein the definition of substituents is given above, or
d) reacting a compound of formula 
with a compound of formula 
to a compound of formula 
wherein Z is Cl, Br, I or xe2x80x94OS(O)2C6H4CH3 and the other definitions of substituents are given above, or
e) reacting a compound of formula 
with a compound of formula 
to a compound of formula 
wherein Z is Cl, Br, I or OS(O)2C6H4CH3 and the definition of the other substituents is given above, or
f) reducing a compound of formula 
to a compound of formula 
wherein the definition of substituents is given above, or
h) modifying one or more substituents R1-R6 or R within the definitions given above, and if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt.
In accordance with process variant a) DIPEA (N-ethyldiisopropyl-amine) is added to a mixture of a compound of formula II, for example methyl-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]amine, and a compound of formula III, for example 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in dichloromethane and the mixture is stirred at temperatures between 35-40xc2x0 C. The desired compound of formula I-1 is isolated after purification in good yields.
Process variant b) describes the reaction of a compound of formula IV with a compound of formula V to a compound of formula I-2. The reaction is carried out in conventional manner, for example in a solvent, such as a mixture of toluene and triethylamine. The mixture is refluxed for about 1 hour.
In accordance with process variant c) a compound of formula I-2 is reduced to a compound of formula I-4. This reaction is carried out with a reducing agent, such as LiAlH4 or BH3.THF, in conventional manner.
Process variant d) describes the reaction of a compound of formula VI with a compound of formula VII to a compound of formula I-2. This reaction is carried out by deprotonation of a compound of formula VI with KHMDS (potassium hexamethyldisilazide) and subsequent addition of a compound of formula VII. A suitable solvent is tetrahydrofuran. The reaction is carried out at room temperature.
In accordance with process variant e) a compound of formula I-5 is prepared. This reaction is carried out by deprotonation of a compound of formula VIII with NaH and subsequent addition of a compound of formula VII. This reaction is carried out in conventional manner.
A further method for the preparation of a compound of this invention is described in process variant f). A compound of formula I-1 is reduced to a compound of formula I-3 in conventional manner, for example with LiAlH4 or BH3.THF.
The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids come into consideration. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methanesulphonates, p-toluenesulphonates and the like are examples of such salts.
The following schemes 1-8 describe the processes for preparation of compounds of formula I in more detail. The starting materials of formulae V, IX, XII, XV, XVI, XXII, XXV, XXVIII, IXXX and XXX are known compounds and maybe prepared according to methods known in the art.
In the schemes the following abbreviations have been used:

The definition of substituents is given above. 
The definition of substituents is given above. 
Z=Cl, Br, I or OS(O)2C6H4CH3 
and the definition of the substituents is given above. 
The definition of substituents is given above. 
Z is Cl, Br, I or xe2x80x94OS(O)2C6H4CH3 and the definition of the other substituents is described above. 
Z is Cl, Br, I or xe2x80x94OS(O)2C6H4CH3 and the definition of the other substituents is given above. 
The definition of substituents is given above. 
The definition of substituents is given above.
As mentioned earlier, the compounds of this invention and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.
The compounds were investigated in accordance with the tests given hereinafter. These tests demonstrate the pharmacological activity of the compounds of this invention as NK-1 receptor antagonists. Such activity is correlated with treatment of pain and depression, for example that related to diseases caused by inflammation or to central nervous system disorders. A pKi in the range of about 8.0 to about 9.8 indicates an especially high affinity.
The affinity of test compounds for the NK1 receptor was evaluated at human NK1 receptors in CHO cells infected with the human NK1 receptor (using the Semliki virus expression system) and radiolabelled with [3H]substance P (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%) leupeptin (8 xcexcg/ml), MnCl2 (3 mM) and phosphoramidon (2 xcexcM). Binding assays consisted of 250 xcexcl of membrane suspension (1.25xc3x97105 cells/assay tube), 0.125 xcexcl of buffer of displacing agent and 125 xcexcl of [3H]substance P. Displacement curves were determined with at least seven concentrations of the compound. The assay tubes were incubated for 60 min at room temperature after which time the tube contents were rapidly filtered under vacuum through GF/C filters presoaked for 60 min with PEI (0.3%) with 2xc3x972 ml washes of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in triplicate in at least 2 separate experiments.
The affinity to the NK-1 receptor, given as pKi, is in the scope of 8.00-9.80 for the preferred compounds. Examples of such compounds are
All the compounds of this invention as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical compositions. The pharmaceutical compositions can be administered orally, e.g. in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of this invention and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragxc3xa9es and hard gelatine capsules.
Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.
Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
Moreover, the pharmaceutical compositions can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
The effective amount for the dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of this invention should be appropriate, although the above upper limit can also be exceeded when necessary.